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Evidence based efficacy of herbal preparations in ageing associated cardiovascular disorders.

Most of cardiovascular disorders start long before the overt clinical manifestations occur. The time lapse for hidden progression of pathological process may take years and even decades. The existing arsenal of pharmaceutical agents does not provide a legal room for physician to perform preventive intervention in the individual who is considered healthy now. Therefore, conventional/official cardiovascular therapy is impossible, since no symptoms, no targets, no indications for active treatment exist. To solve the problem we need to find the ways for pathogenic impact capable effectively prevent the development of disease. Suppression of asymptomatic pathological processes moves to the field of phytotherapy. On one hand, effective phytomedical approach allows for continuous and even lifetime management of subclinical pathology by the means of generally safe agents, which are mainly herbal preparations, and per se represent a step towards the development of true pharmaceutical agents. On the other hand, the solutions suggested by phytomedicine are often underestimated, and, therefore, they meet healthy skepticism but deserve thorough and peer evaluation by the experts. As a result, new paradigm of crosstalk between phytomedicine and pharmaceutical approaches may be developed to fill the niche of effective and pathogenetically-targeted pretreatment and treatment of hidden cardiovascular pathologies, which can eventually result in life-threatening disease. The special issue includes the papers by the experts in the field.

Nine research articles and fifteen review articles were selected for publication in the Special Issue. Accumulating evidences confirm the feasibility of using herbal preparations and herbal medical products in the treatment or prevention of cardiovascular disorders. Saleh Al-Shehabi et al. (2016) believe that further studies, especially clinical ones, are warranted to better define several pharmacological parameters of these herbal products, such as toxicity, tolerability, and efficacy. Although the mechanisms of their action are not very clear, there is enough evidence of their efficacy in various cardiovascular disorders. However, for bringing more objectivity, more systematic, well-designed animal and randomized clinical studies with sufficient sample sizes are necessary to reveal of evidence based efficacy of herbal preparations as Rastogi et al. (2016) state in their review. Potential synergistic and adverse side effects of herbal products' interactions also need to be studied (Rastogi et al., 2016). Koonrungsesomboon and Karbwang (2016) consider that ethical core considerations of prevention research of cardiovascular diseases on herbal medicine involve particular attention on the scientific validity of research, risk-benefit assessments, subject selection and vulnerability, and informed consent.

The special issue contains review articles demonstrating approaches to confirm or refute the efficiency of herbal preparations on the basis of clinical studies. It is known that inflammation and dyslipidemias are associated with many cardiovascular disorders. In systematic review and meta-analysis of five prospective randomized controlled trials, Sahebkar et al. (2016) did not reveal a significant effect of pomegranate juice on plasma C-reactive protein levels. Probably, pomegranate juice does not render essential anti-inflammatory action. In addition, Sahebkar et al. (2016) shown that meta-analysis of randomized controlled trials did not suggest any effect of pomegranate consumption on lipid profile in human. However, Cicero and Colletti (2016a) conclude that rational combinations of phytochemical nutraceuticals with different lipid-lowering activities should provide an alternative to drug treatment in primary cardiovascular disease prevention with mildly added cardiovascular risk and in some statin-intolerant patients. Besides, Shayganni et al. (2016) claim that the results of published papers show that the symptoms of several inflammatory diseases can be inhibited or treated by active ingredients from medicinal plants. According to the data summarized by Schwingshackl et al. (2016) in the umbrella review, garlic preparations possess some positive effects on indicators and biomarkers of cardiovascular diseases, typically without causing any serious side effects.

There are several risk factors grouped in what is called "metabolic syndrome." According to Cicero and Colletti (2016b) treatment strategies for metabolic syndrome should include pharmacological and nonpharmacological options. Some nutraceuticals, when adequately dosed, should improve a number of the metabolic syndrome components. Tome-Carneiro and Visioli (2016) believe that (poly)phenol-based nutraceuticals and functional foods might be indeed used as adjunct therapy of cardiovascular diseases, but additional long-term randomized controlled trials with adequate group volume and with clinically relevant end points are needed to provide unequivocal evidence of their clinical usefulness. Hugel et al. (2016) observed studies indicating that the intake of dietary flavonoids is associated with a decreased risk of cardiovascular disease. The evidence suggests that the dietary intakes of polyphenol-rich products improves vascular health, thereby significantly reducing the risk of hypertension and cardiovascular disease. Giglio et al. (2016) suggest a benefit of bergamot in dyslipidemic and other cardiometabolic disorders, potentially leading to reduced overall cardiovascular risk. Based on in-depth investigation of 10th-18th centuries' manuscripts on Traditional Persian Medicine, Zarshenas et al. (2016) also think that flavonoid-rich preparations from Persian medicine may be selected as considerable herbs for geriatrics with cardiovascular ailments.

Among the review articles of the Special Issue, you can find a description of cellular models and successful examples of their usage for the development of herbal preparations for the prevention and treatment of atherosclerosis (Orekhov and Ivanova, 2016). Using these models Kirichenko et al. (2016) showed that anti-cytokine therapy based on herbal preparations might be a promising direction in moderation of atherogenesis, especially when it begins on the early subclinical stages. The use of herbal preparations with anti-cytokine mechanism of action is the most perspective for timely prevention of atherosclerosis, as they have no significant side effects and can be prescribed for long-term administration.

Research articles describe effects of herbal preparations in the different models and in clinical trials. Mostly, herbal preparations are based on plants used in traditional medicine or common herbal medicine. It was shown clinical efficacy of water extract of arjun tree stem bark (Maulik et al., 2016). The stem bark of arjun tree (Terminalia arjuna (Roxb. ex DC.) Wight and Arn.) is used in Indian system of medicine (Ayurveda) for treatment of various cardiac diseases, including heart failure. Maulik et al. (2016) demonstrated in double-blind, randomized controlled trial that T. arjuna extract did not improve echocardiographic left ventricular ejection fraction in chronic heart failure patients over 12 weeks, although there was improvement in functional capacity, antioxidant reserves and symptom-related quality of life in some patients. Andreadou et al. (2016) evaluated in vivo in cholesterol fed rabbits the potential anti-ischemic and anti-atheromatic activity of Chios Mastic gum, the resin of the trunk and branches of Pistacia lentiscus var. chia, used since antiquity in traditional Greek medicine. Mastic extracts reduced the infarct size in normal animals and possess significant antiatheromatic and hypolipidemic activities in rabbits fed cholesterol enriched diet. In traditional Indian medicine, all parts of Cordia myxa L. plant including the fruit, seed, leaves, root and bark are used in various herbal preparations for the treatment of diabetes mellitus, anti-inflammatory, antimicrobial, cytotoxic, diuretic, anti-atherosclerotic, anti-tumour, anti-fertility, antihistaminic and anti-pyretic. Dhiman et al. (2016) demonstrated that methanolic extract of fruit of Cordia myxa effectively normalized the impaired hemodynamic blood pressure and oxidative stress in rats with induced hypertension. These results corroborate the clinical observations that Cordia myxa possess antihypertensive and anticoagulant activity. Authors suggest that these activities may be due to the antioxidant action. Extract from native to South America and Trinidad plant Campomanesia xanthocarpa Ruiz & Pav. caused anti-inflammatory activity in hypercholesterolemic transgenic mice, with results superior to those obtained with the use of aspirin (Klafke et al., 2016). Garlic is widely used in common herbal medicine. Sobenin et al. (2016) revealed direct antiatherosclerotic effects of long-acting garlic preparation in freeze injury model of atherosclerosis in cholesterol-fed rabbits. These data are in good agreement with the results of randomized double-blind, placebo-controlled clinical studies that have also revealed a direct anti-atherosclerotic effect of this garlic preparation.

Four research papers devoted to research of the mechanisms of pharmacological activity of herbal preparations. So, Phoenix dactylifera L., commonly known as date or date palm and Ajwa, a special variety of Saudi Arabian dates is a rich source of nutrients, fibers and bioactive molecules. While previous studies have shown the therapeutic value of dates in liver and kidney diseases etc., its cardioprotective potential remains elusive. Al-Yahya et al. (2016) investigated the cardioprotective effect of lyophilized Ajwa extract ex vivo as well as in vivo in rats. The authors revealed that Ajwa extract had strong antioxidant, hypolipidimic, cardio-protective, anti-inflammatory and antiapoptotic potential against myocardial damage. This further endorses the use of Ajwa in Arabian traditional medicine against cardiovascular diseases. Prando et al. (2016) evaluated the possible mechanisms involved in the prolonged diuretic activity of ethanol soluble fraction obtained from Echinodorus grandiflorus (Cham. & Schltr.) Michel, native to Brazil, Paraguay, Uruguay, Argentina, Venezuela and Florida. E. grandiflorus is used in Brazilian folk medicine as a diuretic drug. Up to date, no study has evaluated the mechanisms involved in this activity after prolonged administration in rats. The results suggest that the mechanisms through which E. grandiflorus extracts induce prolonged diuresis and reduce blood pressure in rats are mainly related to activation of muscarinic and bradykinin receptors with direct effects on prostaglandins and nitric oxide pathways, Jiang et al. (2016) studied the mechanisms of anti-atherosclerotic effect of artesunate, a derivant from artemisinin from the traditional Chinese herb sweet wormwood (Artemisia annua L.). Artesunate attenuated progression of atherosclerosis lesion formation alone or combined with rosuvastatin through anti-inflammatory effect, resulting in down-regulation of TNF-[alpha] and 1L-6, and further downregulating IL-8 and MCP-1 expressions in aorta of transgenic mice. Rosuvastatin combined with artesunate could more effectively attenuate the progression of atherosclerosis lesions than when treated by one of them, demonstrating that lipid-lowering agents combined with anti-inflammatory agents could provide the greater benefit for cardiovascular disease patients. Finally, Zheng et al. (2016) investigated the anti-cancer effects of Chinese Angelica extract on cell viability, apoptotic and necrotic activities and the mechanism of actions of the active fraction. Chinese Angelica (Angelica dahurica Fisch.ex Hoffm.), native to Siberia, Russia Far East, Mongolia, Northeastern China, Japan, Korea, and Taiwan, is used for other numerous treatments of illnesses such as headaches, relieving nasal obstruction, detoxification of the blood, as a pain reliever, an anti-inflammatory, a laxative, sedative, anti-fungal cream for skin, as well as treating swollen gums and toothaches. Authors showed that the organic extract of A. dahurica decreased significantly the gene expression of p53, Bel, Bax and induced apoptosis via caspase cascade and cell cycle arrest.

Thus, in this issue, a team of international experts discusses the most novel topics on rationale for phytomedicine in subclinical pathologies and chronic cardiovascular diseases. I would like to thank the contributors to this Special Issue for their participation. I do hope that this Special Issue will be helpful for the development of novel approaches for prevention and treatment of cardiovascular disorders.

Guest Editor

Alexander N. Orekhov *

Laboratory of Angiopathology, Institute of General Pathology and

Pathophysiology, Russian Academy of Medical Sciences,

8 Baltiyskaya Street, 125315 Moscow, Russia

* Tel: +7 903 169 08 66; fax: +7 495 415 95 94.

E-mail address:


Al-Yahya. M., Raish, M., AlSaid, M.S., Ahmad, A., Mothana, RA, Al-Sohaibani, M., AlDosari, M.S., Parvez, M.K., Rafatullah, S., 2016. 'Ajwa' dates (Phoenix dactylifera L) extract ameliorates isoproterenol-induced cardiomyopathy through downregulation of oxidative, inflammatory and apoptotic molecules in rodent model. Phytomedicine 23, 1240-1248.

Andreadou, L., Mitakou, S.. Paraschos, S., Efentakis, P., Magiatis, P., Kaklamanis, L., Halabalaki, M., Skaltsounis, L, Iliodromitis, E.K., 2016. Pistacia lentiscus L. reduces the infarct size in normal fed anesthetized rabbits and possess antiatheromatic and hypolipidemic activity in cholesterol fed rabbits. Phytomedicine 23, 1220-1226.

Cicero, A.F., Colletti, A., 2016a, Combinations of phytomedicines with different lipid lowering activity for dyslipidemia management: The available clinical data. Phytomedicine 23,1113-1118.

Cicero, A.F., Colletti, A., 2016b. Role of phytochemicals in the management of metabolic syndrome. Phytomedicine 23,1134-1144.

Giglio, R.V., Patti, A.M., Nikolic, D., Li Volti, G., Al-Rasadi, K., Katsiki, N., Mikhailidis, D.P., Montalto, G., Ivanova, E., Orekhov, A.N., Rizzo, M., 2016. The effect of bergamot on dyslipidemia. Phytomedicine 23, 1175-1181.

Hugel, H.M., Jackson, N., May, B., Zhang, A.L., Xue, C.C., 2016. Polyphenol protection and treatment of hypertension. Phytomedicine 23, 220-231.

Jiang, W., Cen, Y., Song, Y., Li, P., din, R., Liu, C., Zhao, Y., Zheng, J., Zhou, H., 2016. Artesunate attenuated progression of atherosclerosis lesion formation alone or combined with rosuvastatin through inhibition of pro-inflammatory cytokines and pro-inflammatory chemokines. Phytomedicine 23, 1259-1266.

Kirichenko, T.V., Sobenin, I.A., Nikolic, D., Rizzo, M., Orekhov, A.N., 2016. Anti- cytokine therapy for prevention of atherosclerosis. Phytomedicine 23, 1198-1210.

Klafke, J.Z., Pereira, R.L, Hirsch, G.E., Parisi, M.M., Porto, F.G., de Almeida, A.S., Rubin, F.H., Schmidt, A., Beutler, H., Nascimento, S., Trevisan, G., Brusco, L, de Oliveira. S.M., Duarte, M.M., Duarte, T., Viecili, P.R., 2016, Study of oxidative and inflammatory parameters in LDLr-KO mice treated with a hypercholesterolemic diet: Comparison between the use of Campomanesia xanthocarpa and acetylsalicylic acid. Phytomedicine 23, 1227-1234.

Koonrungsesomboon, N., Karbwang, J., 2016. Ethical considerations in clinical research on herbal medicine for prevention of cardiovascular disease in the ageing, Phytomedicine 23, 1090-1094,

Maulik, S.K., Wilson, V., Seth, S., Bhargava, B., Dua, P., Ramakrishnan, S., Katiyar, C.K., 2016. Clinical efficacy of water extract of stem bark of Terminalia arjuna (Roxb, Ex DC.) Wight & Am, in patients of chronic heart failure: a double-blind, randomized controlled trial. Phytomedicine 23,1211-1219.

Orekhov, A.N., Ivanova, E.A., 2016. Cellular models of atherosclerosis and their implication for testing natural substances with anti-atherosclerotic potential. Phytomedicine 23, 1190-1197.

Prando, T.B., Barboza, L.N., Araujo, V.O., Gasparotto, F.M., de Souza, L.M., Lourengo, E.L., Gasparotto Junior, A., 2016. Involvement of bradykinin B(2) and muscarinic receptors in the prolonged diuretic and antihypertensive properties of Echinodorus grandiflorus (Cham & Schltdl.) Micheli. Phytomedicine 23, 1249-1258.

Rastogi, S., Pandey, M.M., Rawat, A.K., 2016. Traditional herbs: a remedy for cardiovascular disorders. Phytomedicine 23, 1082-1089.

Sahebkar, A., Gurban, C., Serban, A., Andrica, F., Serban, M.C., 2016. Effects of supplementation with pomegranate juice on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. Phytomedicine 23,1095-1102.

Sahebkar, A., Simental-Mendla, L.E., Giorgini, P., Ferri, C., Grassi, D., 2016. Lipid profile changes after pomegranate consumption: A systematic review and metaanalysis of randomized controlled trials. Phytomedicine 23,1103-1112.

Saleh Al-Shehabi, T., Iratni, R., Eid, A.H., 2016. Anti-atherosclerotic plants which modulate the phenotype of vascular smooth muscle cells. Phytomedicine 23, 1068-1081.

SchwingshackI, L., Missbach, B., Hoffmann, G., 2016. An umbrella review of garlic intake and risk of cardiovascular disease. Phytomedicine 23,1127-1133,

Shayganni, E., Bahmani, M., Asgary, S., Rafieian-Kopaei, M., 2016. Inflammaging and cardiovascular disease: Management by medicinal plants. Phytomedicine 23, 1119-1126.

Sobenin, I.A., Andrianova, I.V., Lakunin, K.Y., Karagodin, V.P., Bobryshev, Y.V., Orekhov, A.N., 2016. Anti-atherosclerotic effects of garlic preparation in freeze injury model of atherosclerosis in cholesterol-fed rabbits. Phytomedicine 23, 1235-1239.

Tome-Carneiro, J., Visioli, F., 2016. Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomedicine 23, 1145-1174.

Zarshenas, M.M., Jamshidi, S., Zargaran, A., 2016. Cardiovascular aspects of geriatric medicines in traditional Persian medicine; a review of phytochemistry and pharmacology. Phytomedicine 23,1182-1189.

Zheng, Y.M., Shen, J.Z., Wang, Y., Lu, AX, Ho, W.S., 2016, Anti-oxidant and anticancer activities of Angelica dahurica extract via induction of apoptosis in colon cancer cells, Phytomedicine 23, 1267-1274.
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Author:Orekhov, Alexander N.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Editorial
Date:Sep 28, 2016
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